PROJECT SUMMARY
The global rate of HIV infection and the number of AIDS related deaths have dramatically declined due to the
expanding access to combinatorial anti-retroviral therapy (cART). However, the HIV epidemic remains and
there is still no cure for HIV infection. Because cART does not eradicate HIV, while replication-competent
viruses become integrated and silenced proviruses, which can be sporadically reactivated to replenish viral
reservoirs. As a key anatomical “sanctuary site” for HIV infection and persistence/latency, reservoirs in brain
remains a main hurdle for HIV cure. HIV-infected monocytes contribute to viral spread from the periphery blood
to the brain as they can migrate across the blood brain barrier (BBB) and differentiate into microglia in the
central nervous system (CNS). Microglia are a major and stable viral reservoir for persistent/latent HIV
infection in the CNS, even in the presence of cART. Furthermore, HIV-infected microglia release neurotoxic
factors that promote neuroinflammation and contribute to HIV-associated neurocognitive disorders (HAND).
Therefore, characterization of molecular features regulating HIV persistent/latent infection in microglia is
essential for developing effective intervention strategies to control and inhibit HIV in the CNS. Epigenetic
regulation critically determines the faith of HIV proviruses and contributes significantly to HIV latency. The
focus of this project is to investigate the role of host epigenetic regulation in promoting persistent/latent HIV
infection in microglia and target it for preventing HIV lytic reactivation. We have identified a set of Jumonji
domain-containing histone lysine demethylases (KDMs) as HIV latency-promoting genes (LPGs) that
preferentially target histone H3K4/K36 methylation (H3K4/K36me3), which indicates the potential role of
histone demethylation in regulation of HIV latency. In Aim 1, we will investigate the contribution of these KDMs
to promoting HIV latency in human microglia and iPSC-derived microglia containing organoids (MCOs). In Aim
2, encouraged by the KDM studies, we would like to continue the use of our functional genomic and proteomic
expertise to identify other ovel host factors governing HIV latency in microglia by multidisciplinary approaches,
including single-cell CRISPR screen. This is an important issue to address so that we can novel host targets to
develop more potent regimen for reinforcing HIV latency and preventing its resurrection at a cART-free setting
in microglia. Furthermore, we also screened a library of FDA-approved drugs and identify HIV latency-
promoting agents (LPAs), including levosimendan (LSM). In Aim 3, we propose the translational studies to
investigate the repurposing of FDA-approved drugs already used in clinic for treating and blocking HIV
persistent/latent infection in microglia, which likely affect epigenetic processes.